Opioid use disorder (OUD) reached epidemic proportions in the US with more than 2.5 million individuals affected and dramatic increase in unintentional opioid-related overdose deaths. While maintenance with buprenorphine is a leading treatment for opioid-dependent individuals, this is not acceptable to some patients, nor is it universally effective as approximately 50% of individuals treated with buprenorphine continue using illicit opioids and/or drop out during the first 6 months of treatment. Naltrexone, a mu-opioid receptor antagonist, given as extended-release (XR) preparation, offers an alternative approach for patients who have failed prior agonist trials or those who are not suitable or agreeable to agonist maintenance. Naltrexone is fitting for individuals seeking recovery without opioid agonists as it offers the promise of securing abstinence and circumventing the high relapse rates currently observed following opioid detoxification. However, at present time only 50% of patients are successfully retained in treatment with XR-naltrexone over long period of time which limits it protective effects and can be a barrier to a widespread dissemination and acceptance of antagonist-based treatment. In the proposed trial, we will test the effectiveness of a new pharmacological approach to increase the proportion of patients successfully retained on XR-naltrexone by combining it with buprenorphine administered daily. Adding buprenorphine after the patient received XR-naltrexone will not produce mu opioid agonist effect but remaining kappa antagonist effects of buprenorphine may provide additional relief of protracted withdrawal, craving, and mood disturbances persisting in patients treated with XR-naltrexone and possibly contributing to premature treatment discontinuation and relapse. The goal of this five-year study is to test whether addition of buprenorphine will improve treatment retention, reduce opioid craving, and improve mood over the subsequent 6-months of treatment during which participants will receive six XR-naltrexone injections and relapse-prevention therapy. We will conduct a placebo-controlled, double-blind, two parallel arm clinical trial with 1:1 randomization to evaluate the safety and the efficacy of buprenorphine 4 mg/d administered concurrently with XR-naltrexone. Individuals with OUD seeking treatment with naltrexone will be detoxified and after they receive XR-naltrexone they will be randomized to treatment with buprenorphine (N = 60), or placebo (N = 60) with 5 additional doses of XR-naltrexone, given every 4 weeks, and weekly therapy. Buprenorphine (4 mg/d) or placebo will be started after the first XR-naltrexone dose and tapered off after the final XR-naltrexone injection. The primary outcome measure will be the proportion of patients successfully retained to receive six consecutive XR-naltrexone injection. Severity of withdrawal symptoms craving, sleep disturbance, and opioid use will be also measured. If found effective, the combined buprenorphine-XR-naltrexone treatment would be a significant advance in treatment of OUD and would have the potential to expand the population of individuals who benefit from XR-naltrexone.